What specific infection control measures must be adhered to in order to prevent infection in transplant patients - liver transplant?

Specific infection control measures to prevent infection after liver transplantation are not significantly different from those measures employed for patients undergoing other types of solid organ transplantation (SOT).

Specific pathogens with available prophylaxis after liver transplantation

Pathogen

Most common agents used for prophylaxis

Viruses

Varicella-zoster virus (VZV)

Ganciclovir, valganciclovir, acyclovir, valacyclovir, famciclovir

CMV

Ganciclovir, valganciclovir

HSV I/II

Acyclovir, valacyclovir, famciclovir

Fungi

Pneumocystis jiroveci

Trimethoprim-sulfamethoxazole

Candida spp.

Fluconazole

What are the key conclusions from available clinicaltrials or meta-analyses related to transplant patients - liver transplant that guide infection control practices and policies?

Few clinical trials or meta-analyses are available that directly address infection control measures related to liver transplantation. Relevant clinical trials are summarized here.

Cytomegalovirus disease prevention

The following are key principles that guide care related to CMV disease prevention among liver transplant recipients.

The risk of developing CMV disease after liver transplantation is directly related to the serological status of the donor and recipient, with serodiscordance (i.e., donor CMV IgG-positive/recipient CMV IgG-negative, or D+/R-) carrying the greatest risk.

Two general prevention strategies, prophylaxis and pre-emption, have been used for CMV disease prevention in SOT. Prophylaxis involves administration of antiviral drug therapy to all patients, regardless of their relative risk of disease. Pre-emption involves monitoring patients for evidence of CMV reactivation using virus-specific markers such as pp65 antigenemia or nucleic acid testing (NAT); patients with CMV reactivation are given antiviral therapy until these markers resolve. A hybrid approach is used by many transplant centers that involves an initial period of universal prophylaxis followed by monitoring and pre-emption.

Currently these strategies, prophylaxis and pre-emption, appear to be equally effective at preventing CMV disease in SOT, including liver transplant recipients.

Ganciclovir (5mg/kg IV daily, adjusted for renal clearance) and valganciclovir (900mg per os daily, adjusted for renal clearance) are currently the most effective antiviral drugs used for CMV disease prevention in SOT.

When used for prophylaxis, the duration of antiviral administration most commonly used is 100 days. However, the IMPACT trial demonstrated that extending prophylaxis to 200 days for serodiscordant (CMV D+/R-) kidney transplants reduced the risk of CMV disease for as long as 2 years post-transplant. Thus, most experts now recommend extending CMV antiviral prophylaxis to 200 days in this patient population (i.e. CMV D+/R-) if this strategy is used. It is not known if the same benefits apply to liver transplant recipients.

Herpes simplex virus I/II disease prevention

The period of greatest risk for reactivation and disease from HSV in liver transplant recipients occurs in the first month following transplantation. All HSV-seropositive recipients, or seronegative recipients receiving an organ from a seropositive donor, should receive prophylaxis for HSV disease for at least 1 month post-transplant.

CMV prophylaxis will also prevent HSV disease.

If CMV prophylaxis is not administered, liver transplant recipients should receive one of the following agents for HSV prophylaxis:

Acyclovir 400-800mg per os, twice a day.

Valacyclovir 500mg per os, twice a day.

Famciclovir 500mg per os, twice a day.

Varicella zoster virus disease prevention

Regimens used for CMV and HSV prophylaxis also provide protection for VZV reactivation. These regimens are typically not used for long durations, while the risk for VZV reactivation persists for the lifetime of the patient. No current recommendations exist for the routine prophylaxis of VZV in SOT recipients beyond the use of antivirals for CMV and HSV.

Pneumocystis jirovecipneumonia prophylaxis

Routine administration of Pneumocystis jiroveci prophylaxis (PJP) is recommended for transplant centers with a PJP incidence of 3-5%. The following regimens are recommended by experts, with most clinical trial experience from trials in HIV/AIDS patients:

Trimethoprim-sulfamethoxazole (TMP-SMX): 160mg TMP/800mg SMX (DS tablet) per os three times weekly. Some centers use one DS tablet twice weekly, while others use single strength (SS, 80mg TMP/400mg SMX) 2-3 times weekly. TMP-SMX should be considered the first-line agent for PJP prophylaxis.

Dapsone 100mg per os daily.

Atovaquone 1500mg per os daily.

Pentamidine 300mg aerosol via nebulizer once every 28 days.

Clindamycin 300mg per os daily/pyrimethamine 15mg per os daily.

The duration of PJP prophylaxis should be 6-12 months, depending on the net state of immune suppression.

Infection control and practices related to the prevention of infections caused by pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Clostridium difficile, or drug-resistant gram-negative bacteria are currently not different from other populations of hospitalized or surgical patients.

What are the consequences of ignoring the concepts related to transplant patients - liver transplant?

Implementation of specific infection control practices as they relate to liver transplantation is critical for the survival and well being of the transplanted patient. As an example, the incidence of CMV disease one year after liver transplantation in patients without prophylaxis was 31% in a randomized, placebo-controlled trial of CMV immune globulin.

What other information supports the key conclusions of studies of or advice from transplant patients - liver transplant (e.g., case control studies and case series)?

Summary of current controversies.

Prevention of IFI after liver transplantation - which antifungal agent is best?

What is the impact of controlling infections in transplant patients - liver transplant relative to the control of infections in other patient populations?

The major difference between the impact of infection control among liver transplant patients and infection control among other patient populations is the magnitude of benefit reaped by preventing infections related to or worsened by the immune suppression necessary to successfully transplant allogeneic organs.

Patients requiring liver transplantation are already at a higher risk for a variety of infections because of the immunological defects associated with acute or chronic liver disease. Although many of these immune deficits are corrected by transplantation of a healthy donor liver (e.g., restoration of complement component synthesis), the immunosuppression required to prevent host rejection of the new liver introduces new immune challenges.

Adherence to good infection control practices as they relate to liver transplant patients offset the infectious burden imposed by this immunosuppression.

Controversies in detail.

Prophylaxis: all patients at risk of CMV disease are given preventive therapy.

Arguments for this strategy: Efficacy of prophylaxis at preventing CMV disease, especially among CMV D+/R- recipients, the potential efficacy to prevent bacterial and fungal infections (in addition to CMV disease), the lack of need to perform surveillance testing during prophylaxis, and a theoretical reduction in the risk of selecting for drug-resistant CMV.

Problems: The cost and toxicities associated with exposure of all at-risk patients to drug therapy, suppression of low-level viral replication that may engender an effective host immune response, risk for late-onset CMV disease after prophylaxis is discontinued.

Pre-emption: monitoring patients for evidence of asymptomatic CMV replication, with initiation of therapy only when CMV replication is detected.

Arguments for this strategy: Efficacy of pre-emption at preventing CMV disease, reduced drug exposure (with associated reductions in cost and toxicities), potential for better "priming" of the host immune response against CMV, reduction in late CMV disease incidence.

Problems: False negative testing, leading to missed early CMV disease, logistically more difficult due to need for intermittent testing, lack of standardized threshold for initiation of drug therapy, potential for selection of drug-resistant CMV.

2. Prevention of IFIs after liver transplantation - which antifungal agent is best and who should receive antifungal prophylaxis?

Several new antifungal agents have become available in the past decade, including the echinocandins (caspofungin, micafungin, and anidulafungin), newer azoles (voriconazole and posaconazole), and lipid formulations of amphotericin B. Fluconazole has become the most commonly used antifungal agent post-liver transplant, but this agent lacks activity against molds and many non-albicans Candida species, especially C. glabrata.

As a consequence of the "holes" in the spectrum of antifungal activity for fluconazole, and the toxicities associated with using amphotericin B deoxycholate, many transplant clinicians have changed from these agents to newer antifungals for use as post-transplant prophylaxis for IFIs. Some centers only provide antifungal prophylaxis for patients at high-risk for IFIs post-transplant (ex: kidney failure, large blood product requirement), while others provide prophylaxis to all liver transplant recipients.

Table VII summarizes select studies that have focused on the use of these newer agents for prophylaxis or address "targeted prophylaxis" to high-risk populations.
Table VII.

Newer agents for prophylaxis/targeted prophylaxis

Authors/year of publication

Study design

Results/conclusions

Comments

Tollemar et al. 1995

RCT

LAmB (1mg/kg/d) for 5 days post-transplant protected from IFI during 1st month compared to placebo.

Trial designed to enroll 300 patients, closed early due to insufficient enrollment. High-risk defined as > or =2 of following: choledochojejunostomy, retransplant, intraoperative use of >40 units of blood products, re-operation within 5 days for bleeding/leak/vascular insufficiency/graft failure, preoperative creatinine >2mg/dL or dialysis +/- 2 days of transplant, Candida colonization.